Extended release compositions comprising as active compound venlafaxine hydrochloride

ABSTRACT

The present invention relates to an extended release composition comprising as active compound Venlafaxine Hydrochloride, in which Venlafaxine Hydrochloride is coated on a non pareil inert core, which coated core is then coated with polymeric layer which enables the controlled release of the Venlafaxine Hydrochloride.

The present invention relates to extended release compositions comprising as active compound venlafaxine hydrochloride.

Venlafaxine hydrochloride is an antidepressant having formula (1)

being designated (R/S)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)-ethyl]cyclohexanol hydrochloride or (±)-1-[a](dimethylamino)-methyl]p-methoxybenzyl cyclohexanol hydrochloride, having the empirical formula of C₁₇H₂₇NO₂ hydrochloride and molecular weight of 313.87.

Venlafaxine hydrochloride is a white to off-white crystalline solid with a solubility of 572 mg/ml in water (adjustment to ionic strength of 0.2 M with sodium chloride). Its octanol:water (0.2 M sodium chloride) partition coefficient 0.43. EFFEXOR XR, the Brand product, is formulated as an extended release capsule for once-a-day oral administration.

The drug release has so far been controlled by diffusion through the coating membrane on the spheroids and is not pH-dependent. Known capsules containing venlafaxine hydrochloride comprise amounts equivalent to 37.5 mg, 75 mg, or 150 mg of venlafaxine. The inactive ingredients are mainly cellulose, ethylcellulose, gelatin, hydroxypropylmethylcellulose, iron oxide, and titanium dioxide.

Controlled or extended release dosage forms of medicament are conventionally produced as hydrogel matrix-based tablets. With this technology, the controlled release dosage forms are simply prepared by mixing the active material with the appropriate rate of controlling polymers and then that mixture is compressed into the desired controlled release tablets. The rate-controlling polymers are normally termed as hydrogels. Examples of such polymers are cellulose ethers such as ethyl cellulose or hydroxypropylcellulose. Patents describing preparation methods of such dosage forms are described, for example, in U.S. Pat. Nos. 4,966,768 and 4,389,393.

In some cases; for example with very water soluble active materials and with relatively high doses, it is not feasible to produce tablets which enable appropriate control on the drug's release. This is the case, for example with venlafaxine hydrochloride.

In such a case, a suitable approach is encapsulating the drug and producing extended release capsule dosage forms. When preparation of such dosage forms is considered, the preferred way is to mix the active ingredient with at least one binding agent to form a uniform mixture which is later moistened with water or with an appropriate organic solvent to form an extrudable plastic mass, from which small particles, cylindrical in shape (1 mm diameter), of drug/matrix are extruded, chopped into appropriate lengths and converted to spheroids using spheronization equipment. These spheroids are further dried and then film-coated with an appropriate polymer to form a film with the desired release patterns. The most widely used excipient in the extruding process is microcrystalline cellulose in its different grades; usually, water is used for the wetting process.

Polymers widely used for coating are ethyl cellulose or EUDRAGIT (ammonio methacrylate copolymer, type A or B). Water-soluble ingredients are normally mixed with the ethyl cellulose or with other hydrophobic polymers, such as pore forming agents, to assist the control on the drug's release through the hydrophobic coating layer. The water-soluble ingredients, such as hydroxypropylcellulose or polyethylene glycol, may serve as plasticizers as well.

Venlafaxine hydrochloride has so far been formulated into a controlled release dosage form with the ability to provide in a single dose a therapeutic blood serum level of the drug over a twenty four hour period. By this method, tighter plasma, therapeutic range control can be obtained and multiple dosing is avoided in this manner. The sharp peaks and troughs in blood plasma drug levels are avoided as well.

With the conventional release dosage forms of venlafaxine hydrochloride (tablets), peak blood plasma levels appeared after 2-4 hrs, in contrast to the extended release dosage forms, when plasma levels of venlafaxine hydrochloride rose after administration for between five to eight hrs (average −6) and then begin to fall through a protracted, substantially linear decrease from the peak plasma level for the reminder of the period, maintaining therapeutic level of the drug during the entire twenty four hours period.

In WO 99/22724 (AHP, Sherman), a detailed description of preparing an encapsulated dosage form (coated spheroids) of venlafaxine hydrochloride is provided. By the method described therein, a spheroid core is prepared by extruding and spheronizing a mixture of the drug with microcrystalline cellulose, and then coating it with an ethyl cellulose hydroxypropylcellulose mixture:

This dosage form provides an extended release product with the following in vitro dissolution specifications:

Time (hrs) Average % venlafaxine HCL release 2 <30 4 30-55 8 55-80 12 65-90 24 >80

These dissolution characteristics are pH- and RPM-independent.

In the present invention, an alternative once daily bioequivalent formulation to the innovator's one (EFFEXOR XR, described in WO 99/22724) has been developed.

As already mentioned, with high dose water-soluble product, such as venlafaxine hydrochloride (150 mg), the usual preferred way of encapsulating it is by preparing and coating appropriate beads, using the extrusion spheronization process.

In the present invention, the microencapsulation has been changed, i.e., is being performed by layering the drug over an inert nonpareil core, and then coating it with an appropriate polymeric mixture.

The present invention thus consists in an extended release composition comprising as active compound venlafaxine hydrochloride, in which venlafaxine hydrochloride is coated on a nonpareil inert core, which coated core is then coated with a polymeric layer which enables the controlled release of the venlafaxine hydrochloride.

The composition preferably comprises 30-60% of venlafaxine hydrochloride per weight of the total dosage form.

In a preferred embodiment of the present invention, the venlafaxine hydrochloride is suitably connected to a binder; said binder may be, e.g., polyvinylpyrrolidone (povidone), hydroxypropylcellulose, hydroxypropylmethylcellulose, etc. The composition preferably comprises 0.5%-10% of the binder per weight of the total dosage form.

Advantageously the nonpareil inert core is an inert sugar core, a microcrystalline cellulose, or the like. The composition preferably comprises 30-60% of the core per weight of the total dosage form.

Alternatively, the drug might be sprayed as it is and the water is then used as binding enhancement agent.

Advantageously, the coated core is coated with an isolating/protecting/separating layer, which layer is suitably composed of polymers such as polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, carrageenan, GMS, etc. The composition preferably comprises 0.5-10% of the isolating layer per weight of the total dosage form.

The core or the isolating layer is coated then with an additional polymeric layer which enables the controlled release of venlafaxine hydrochloride. Said additional polymeric layer is composed, e.g., of a hydrophobic polymer mixed with an appropriate hydrophobic or hydrophilic plasticizer. Said polymeric layer is suitably sprayed over the coated nonpareil layer or over the isolating layer.

Appropriate coating polymers are, e.g. EUDRAGIT, cellulose derivatives such as hydroxypropylmethylcellulose, ethyl cellulose, cellulose acetate, etc. Their suitable plasticizers are, e.g., castor oil, dibutyl sebacate, glyceryl monostearate, diethyl phthalate, glyceryl triheptanoate, triethylcitrate, etc.

The coating polymeric layer may also be a wax-based coating.

The composition preferably comprises 2-15% of the hydrophobic polymer per weight of the total dosage form, and preferably 0.1-2% per weight of the hydrophobic plasticizer per weight of the total dosage form.

The above processes are conventional processes that may be performed in a fluidized bed coater with a bottom spraying mechanism.

In the composition according to the present invention, preferably not more than 40% of the drug is released after two hours, not more than 60% released after 4 hours, and not more than 80% after 8 hours.

The compositions obtained are suitably, e.g., filled into hard gelatin capsules or compressed into'tablets.

This formulation has an identical in vitro dissolution profile as EFFEXOR XR (see Sherman, WO99/22724). They are not sensitive to any changes in dissolution conditions. It is bioequivalent to EFFEXOR XR 150 mg caps.

The coating process being used to produce the composition according to the present invention is more efficient than the method being used in the Sherman patent. Moreover, it enables the preparation of the drug in a single type of equipment, e.g. a fluidized bed coater.

The present invention will now be illustrated with reference to the following examples, without being limited by them.

The process for preparing the composition according to the present invention is suitably performed as follows (all temperatures are given in degrees centigrade):

-   -   a. When venlafaxine hydrochloride is connected to a binder the         venlafaxine hydrochloride is connected to the binder by methods         known per se.     -   b. Stage 1     -    Coating the nonpareil core with the venlafaxine hydrochloride         (advantageously connected with a binder) is performed at an         inlet temperature of 45-55° (preferably at 50°) at an outlet         temperature of 35-45° (preferably at 40°).     -    At the end of the spraying process, the composition is dried         for 10 minutes without nozzle with 30 cfm air flow.     -   c. Stage 2     -    The coated core obtained in Stage 1 is coated with the         insulating layer at an inlet temperature of 60°+/−3° at an         outlet temperature of 50°+/−2°.     -   d. Stage 3 (when an insulating layer is present in Stage 2)     -    The core is coated with a further preliminary layer; the         conditions of said coating are:     -    Inlet temp: 50°+/−2°     -    Outlet temp: 40°+/−5°

EXAMPLE NO. 1 Without Binder

Stage 1: Components—Nonpareils 25/30 150 gr

-   -   Venlafaxine hydrochloride 37.5 gr     -   H₂O 150 gr.

Stage 2: Components—150 gr layered pellets from stage 1

-   -   ETHOCEL 45 cp 15 gr     -   METHOCEL 5 cp 1 gr     -   Ethanol BP 300 gr         At the end of the spray process the composition is dried for 10         minutes without nozzle with 30 cfm.

EXAMPLE NO. 2

Stage 1: components—Nonpareils (inert sugar pellets) 150 gr

-   -   Povidone K-30 3.3 gr.     -   Venlafaxine hydrochloride 165 gr.     -   Ethanol BP 670 gr.

Stage 2: components—150 gr. layered pellets from stage 1

-   -   ETHOCEL 45 cp 15 gr     -   METHOCEL 5 cp 1 gr     -   Ethanol BP 300 gr         The coating process was performed in a “4” fluidized bed coater         made by Coating Place Inc. USA.

EXAMPLE NO. 3

Stage 1: components—Nonpareils 25/30 150 gr

-   -   Venlafaxine hydrochloride 37.5 gr     -   Povidone K-30 0.75 gr     -   Ethanol BP 160 gr

Stage 2: components—150 gr layered pellets from stage 1

-   -   EUDRAGIT RS 30 D 150 gr     -   Triethyl citrate 9 gr     -   Glycerol monostearate 2.25 gr     -   Polysorbate 80 1 gr     -   Water 140 gr         The coating process was performed in a “4” fluidized bed coater,         made by Coating Place Inc. USA.

EXAMPLE NO. 4

Stage 1: components—Nonpareils 25/30 150 gr.

-   -   Povidone K-30 0.75 gr.     -   Venlafaxine-HCL 37.5 gr.     -   Ethanol-BP 160 gr.

Stage 2: components—150 gr. pellets from stage 1.

-   -   EUDRAGIT RS 30 D 150 gr.     -   EUDRAGIT RL 30 D 15 gr.     -   Triethyl citrate 9 gr.     -   Glycerol monostearate 2.25 gr.     -   Polysorbate 80 1 gr     -   Water 140 gr.         All processes were performed in a “4” fluidized bed coater, made         by Coating Place Inc. USA.

EXAMPLE NO. 5

Stage 1: components—150 gr. Nonpareils 25/30

-   -   Povidene K-90 4.5 gr.     -   Venlafaxine-HCL 150 gr.     -   Ethanol BP 670 gr.     -   Water 110 gr

Stage 2: components—150 gr. pellets from stage 1

-   -   Povidone K-30 3.75 gr.     -   Ethanol-absolute 60 gr.

Stage 3: components—Pellets from stage 2

-   -   ETHOCEL 100 cp 8 gr.     -   Dibutyl sebacate 0.8 gr.     -   Ethanol-absolute 300 gr.

In the above examples, EUDRAGIT RS 30 D is poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:20.1 . . . EUDRAGIT RL 30 D is poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.2. ETHOCEL is ethyl cellulose and METHOCEL is methyl cellulose. 

1. A pH-independent extended release dosage form, comprising: venlafaxine hydrochloride in an amount of 30-60% based on the total weight of the dosage form; said venlafaxine hydrochloride being coated on a nonpareil inert core, said nonpareil inert core comprising 30-60% based on the total weight of the dosage form; the venlafaxine hydrochloride being optionally connected to a binder in a binder amount of 0.5-10% based on the total weight of the dosage form; an isolating layer coating said venlafaxine hydrochloride and comprising 0.5-10% based on the total weight of the dosage form, said isolating layer being selected from the group consisting of polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, carrageenan and GMS; and a controlled release layer coated over said isolating layer, said controlled release layer comprising a controlled release polymer optionally mixed with a plasticizer, said controlled release polymer comprising 2-15% based on the total weight of the dosage form, said controlled release polymer being selected from the group consisting of ammonio methacrylate copolymer, hydroxypropylmethylcellulose, ethyl cellulose, and cellulose acetate, and said optional plasticizer, when present, comprising 0.1-2% based on the total weight of the dosage form; wherein said layers cause the venlafaxine hydrochloride to be released in a pH-independent manner over an approximately 24 hour period after oral administration.
 2. The unit dosage form of claim 1, wherein at least one of said controlled release layer, said isolating layer, and said optional binder, when present, comprises hydroxypropylmethylcellulose.
 3. A pH-independent extended release composition, comprising: a nonpareil inert core; a venlafaxine hydrochloride layer coating said inert core, said venlafaxine hydrochloride comprising 30-60% based on the total weight of the composition; and a controlled release polymer layer coating said venlafaxine hydrochloride layer, said controlled release polymer being selected from the group consisting of ammonio methacrylate copolymer, hydroxypropylmethylcellulose, ethyl cellulose, and cellulose acetate, said controlled release polymer layer comprising 2-15% based on the total weight of the composition, wherein said layers permit pH-independent release of the venlafaxine hydrochloride over an extended time period after oral administration.
 4. The composition according to claim 3, further comprising an isolating layer coating said venlafaxine hydrochloride layer, said isolating layer being selected from the group consisting of polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, carrageenan and GMS, and providing at least one function of isolating, protecting and separating the venlafaxine hydrochloride layer from the hydrophobic polymer layer.
 5. The composition according to claim 4, wherein the isolating layer comprises a polymer selected from the group consisting of polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, and carrageenan.
 6. The composition according to claim 4, wherein the isolating layer is 0.5-10% based on the total weight of the composition.
 7. The composition according to claim 3, wherein the venlafaxine hydrochloride layer further comprises a binder.
 8. The composition according to claim 7, wherein the binder is selected from the group consisting of polyvinylpyrrolidone, hydroxypropylcellulose and hydroxypropylmethylcellulose.
 9. The composition according to claim 7 wherein the binder is 0.5-10% based on the total weight of the composition.
 10. The composition according to claim 3, wherein the controlled release layer further comprises a plasticizer.
 11. The composition according to claim 10, wherein the plasticizer is 0.1-2% based on the total weight of the composition.
 12. The composition according to claim 10, wherein the plasticizer is selected from the group consisting of castor oil, dibutyl sebacate, glyceryl monostearate, diethyl phthalate, glyceryl triheptanoate, hydroxypropyl cellulose, polyethylene glycol, and triethyl citrate.
 13. The composition according to claim 3, wherein the nonpareil inert core is an inert sugar core or a microcrystalline cellulose core.
 14. The composition according to claim 13, wherein the core is 30-60% based on the total weight of said composition.
 15. A method for preparing an extended release composition in accordance with claim 3, comprising: providing the nonpareil inert core; coating the nonpareil inert core with a layer of the venlafaxine hydrochloride; and coating the venlafaxine hydrochloride layer with the controlled release layer.
 16. The composition of claim 1, wherein the isolating layer comprises polyvinylpyrrolidone, the controlled release polymer is ethyl cellulose and the controlled release layer further comprises a dibutyl sebacate plasticizer.
 17. The unit dosage form of claim 1, wherein said binder is selected from the group consisting of polyvinylpyrrolidone, hydroxypropylcellulose, and hydroxypropylmethylcellulose.
 18. A pH-independent extended release dosage form having specified dissolution characteristics, comprising: venlafaxine hydrochloride in an amount of 30-60% based on the total weight of the dosage form; said venlafaxine hydrochloride being coated on a nonpareil inert core, said nonpareil inert core comprising 30-60% based on the total weight of the dosage form; the venlafaxine hydrochloride being optionally connected to a binder in a binder amount of 0.5-10% based on the total weight of the dosage form wherein said binder, when present, is selected from the group consisting of polyvinylpyrrolidone, hydroxypropylcellulose and hydroxypropylmethylcellulose; an isolating layer coating said venlafaxine hydrochloride and comprising 0.5-10% based on the total weight of the dosage form, said isolating layer being selected from the group consisting of polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, carrageenan and GMS; and a controlled release layer coated over said isolating layer, said controlled release layer comprising a controlled release polymer mixed with a plasticizer, said controlled release polymer comprising 2-15% based on the total weight of the dosage form, said controlled release polymer being selected from the group consisting of ammonio methacrylate copolymer, hydroxypropylmethylcellulose, ethyl cellulose, and cellulose acetate, and said plasticizer comprising 0.1-2% based on the total weight of the dosage form; the parameters being selected so as to control release of the venlafaxine hydrochloride over an approximately 24 hour period in a manner that the following pH and rpm independent in vitro dissolution specifications are obtained: Time (hrs) Average % venlafaxine HCl release 2 <30 4 30-55 8 55-80 12 65-90 24 >80


19. A method for preparing a pH-independent extended release dosage form having specified dissolution characteristics, which dosage form comprises venlafaxine hydrochloride in an amount of 30-60% based on the total weight of the dosage form; said venlafaxine hydrochloride being coated on a nonpareil inert core, said nonpareil inert core comprising 30-60% based on the total weight of the dosage form; the venlafaxine hydrochloride being optionally connected to a binder in a binder amount of 0.5-10% based on the total weight of the dosage form wherein said binder, when present, is selected from the group consisting of polyvinylpyrrolidone, hydroxypropylcellulose and hydroxypropylmethylcellulose; an isolating layer coating said venlafaxine hydrochloride and comprising 0.5-10% based on the total weight of the dosage form, said isolating layer being polyvinylpyrrolidone; and a controlled release layer coated over said isolating layer, said controlled release layer comprising a controlled release polymer mixed with a plasticizer, said controlled release polymer comprising 2-15% based on the total weight of the dosage form, said controlled release polymer being ethyl cellulose, and said plasticizer comprising 0.1-2% based on the total weight of the dosage form, said plasticizer being dibutyl sebacate; the parameters being selected so as to control release of the venlafaxine hydrochloride over an approximately 24 hour period in a manner that the following pH and rpm independent in vitro dissolution specifications are obtained: Time (hrs) Average % venlafaxine HCl release 2 <30 4 30-55 8 55-80 12 65-90 24 >80

said process comprising: providing the nonpareil inert core: coating the nonpareil inert core with said layer of the venlafaxine hydrochloride; coating the venlafaxine hydrochloride layer with said isolating layer; and coating the isolating layer with said controlled release layer. 